Synthesis and pharmaceuticals of novel 9-substituted-1, 5-dichloroanthracene analogs

ABSTRACT

The invention relates to novel anthracene compounds useful in the treatment of allergic, inflammatory conditions, tumor conditions and therapeutic compositions containing such compounds. The compounds of the present invention are 9-acyloxy-substituted 1,5-dichloroanthracene or analogs thereof. According to the practice of the invention, there are provided 9-acyloxy substituted 1,5-dichloroanthracene compounds according to formula III:                    
     wherein R represents a straight or branched chain alkyl group having 1 to 6 carbons which may be substituted with one or more groups of R 1 , or R represents phenyl or benzyl which may be substituted with one or two groups of R 2 ; wherein R 1  is selected from the group consisting of halogen, —NO 2 , —OCH 3 , OCH 2 CH 3 , and —OCH 2 CH 2 CH 3 ; and wherein R 2  is selected from the group consisting of a straight or branched chain alkyl group having 1 to 4 carbons, halogen, —NO 2 , —OCH 3 , —OCH 2 CH 3 , and —OCH 2 CH 2 CH 3 .

RELATED APPLICATION

This application is a continuation-in-part of U.S. patent applicationSer. No. 09/290,865 now abdn, filed on Apr. 14, 1999, which is hereinincorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel anthracene compounds useful in thetreatment of allergic, inflammatory conditions, tumor conditions andtherapeutic compositions containing such compounds. The inventionrelates also to the therapeutic compositions effective at low dose withlow irritancy. These anthracene compounds possess antitumor,antiproliferative, antipsoriatic, antiinflammatory, or antioxidantactivity.

2. Description of the Prior Art

The discovery of the antitumor activity of1,4-bis[(aminoalkyl)amino]anthracene-9, 10-diones such as ametantrone(1) and mitoxantrone (2) (FIG. 1) (Zee-Cheng, R. K. V. et al., J. Med.Chem., 21, 291-294 (1978); Zee-Cheng, R. K. V. et al., J. Pharm. Sci.,71, 708-709 (1982); Murdock, K. C. et al., J. Med. Chem., 22, 1024-1030(1979)) has led to numerous physicochemical and pharmacological studieson the tumoricidal mechanisms of these chemotypes. Krapcho, A. P. etal., J. Med. Chem., 341, 2373-2380 (1991); Morier-Teissier, E. et al.,J. Med. Chem., 36, 2084-2090 (1993). Additional references disclose 1,4-and 2,6-disubstituted or regioisomeric amidoanthracene-9,10-dionederivatives as inhibitors of human telomerase. Perry, P. J. et al., J.Med. Chem., 41, 3253-3260 (1998) and Perry, P. J. et al., J. Med. Chem.,41, 4873-4884 (1998).

Although the active mechanism of the antitumor activity of theanthracene-9,10-diones such as ametantrone (1) and mitoxantrone (2) isprobably multimodal in nature, a number of studies have indicated thatan intercalative interaction with DNA may be a major cellular event.Denny, W. A., Anti-Cancer Drug Design, 4, 241-263 (1989). Antitumorquinones represent the second largest class of clinically approvedanticancer agents in the U.S.A., second only to the chloroethylalkylating agents. They have been selected from the large number ofnaturally occurring quinones (Moore, H. W et al., Drugs Expl. Clin.Res., 12, 475-494, (1986)) and from synthetic quinones. Bruce, J. M.ed., Benzoquinones and Related Compounds, Vol. 3, Part 4, 1-306, (1974).The planar tricyclic system is known to intercalate into DNA base pairsand interfere in the transcription and replication processes of thecell. Johnson, R. K. et al., Cancer Treat. Rep., 63, 425-439 (1979);Lown, J. W. et al., Biochemisty, 24, 4028-4035 (1985). The DNA bindingaffinity (quantified as a binding affinity constant) and thedissociation rate constant for the DNA-ligand complex have beenevaluated. Drug-DNA binding constants for ametantrone (1), mitoxantrone(2) and related congeners with calf thymus DNA show a large sensitivityto the position and number of the OH substitutions and the nature of thecharged side chain. Denny, W A., Anti-Cancer Drug Design, 4, 241-263(1989).

Normal human cells undergo a finite number of cell divisions andultimately enter a nondividing state called replicative senescence.During successive rounds of cell division, the end-replication problemresults in telomere shortening and ultimately senescence. As such, theloss of telomeric repeats after each round of cell division has beenlikened to a “biological clock” limiting the proliferative life span ofnormal somatic cells. Harley, C. B. et al., Nature, 345, 458-460 (1990).Consequently, telomerase has been proposed as a potentially highlyselective target for the development of a novel class ofantiproliferative agents. However, in order for a therapeutic treatmentto be effective, both the inflammatory and hyperproliferative aspects ofthe condition must be addressed. Substantial evidence suggests that freeradicals and active oxygen species play a key role in both thetherapeutic activity and side effects of anthracenone derivatives.

Anthraquinone-based compounds currently occupy a prominent position incancer chemotherapy, with the naturally occurring aminoglycosideanthracycline doxorubicin and the aminoanthraquinone mitoxantrone bothbeing in clinical use. These 1,5-dichloro-9(10H)-anthracenone compoundscontain alkylacyl or arylacyl moieties at the C-9 position resulting inenhanced antiproliferative activity of the compounds. These blockedcompounds may be further modified by introducing the phenolic form ofthe arylacyl or alkylacyl substituent.

As noted above, cancer is typically characterized by hyperproliferativecomponent. There is thus a continuing need for effective compounds thataddress these aspects of cancer disease.

SUMMARY OF THE INVENTION

The present invention is directed to novel9-substituted-1,5-dichloroanthracene compounds and salts thereof havingtherapeutic utility with respect to allergic or inflammatory or tumorconditions. In particular, many of the improved anthracene compoundsprovided for according to the invention are effective at lowconcentrations for the treatment of patients suffering from allergic orinflammatory or tumor conditions. Because these compounds may beadministered at low concentrations, the undesirable allergic orinflammatory effects caused in whole or in part by free radicals oractive oxygen species that are generated by anthracenone compounds aresubstantially eliminated.

Accordingly, in one embodiment of the invention, there is provided ananthracene compound according to Formula III below, said compoundcontaining a substituent R, wherein R represents a branched or straightchain alkyl group having from 1 to 4 carbon atoms, said alkyl groupbeing substituted with at least one substituent selected from carboxyl,carboxyl ester, hydroxy, phenyl, benzyl, substituted benzyl andsubstituted phenyl groups.

In a preferred embodiment of the invention, R represents a substitutedphenyl group having at least one substituent selected from methyl,halogen and nitro groups. In another preferred embodiment, R representsa straight or branched chain alkyl group having 1 to 4 carbon atoms,which may contain a substituent selected from acyl and phenyl groups.Additionally, there are provided compounds which are functional analogsof the compounds of Formula III.

As aforementioned, therapeutic compositions of the invention areeffective at dosages that substantially eliminate the adverseinflammatory or irritancy effects associated with the use ofanthracenone and related compounds. Accordingly, there is provided atherapeutic composition comprising a therapeutically effective amount ofat least one compound of the invention and a pharmaceutically acceptablecarrier. These compounds of the invention have antiproliferative effectsand antineoplastic effects.

Further additional representative and preferred aspects of the inventionare described below according to the following detailed description ofthe invention.

DESCRIPTION OF THE DRAWINGS

FIG. 1 Shows the structure of prior art anthraquinonic derivatives.

FIG. 2 is an outline of the synthesis of the9-substituted-1,5-dichloroanthracene compounds.

FIG. 3: Perspective view of the molecular structure of compound (3o).

DETAILED DESCRIPTION OF THE INVENTION

As set forth above, the compounds of the invention are9-acyloxy-1,5-dichloroanthracene analogs. According to of the invention,there are provided 9-substituted-1,5-dichloroanthracene compoundsaccording to Formula III.

wherein R represents a straight or branched chain alkyl group having 1to 6 carbon atoms, phenyl or benzyl, wherein the alkyl group may besubstituted with one or more groups R₁ and the phenyl or benzyl groupmay be substituted with one or two groups R₂. R₁ is a group selectedfrom halogen, NO₂, CH₃O, CH₃CH₂O, and CH₃CH₂CH₂O. R₂ is a group selectedfrom a straight or branched chain alkyl group having 1 to 4 carbonatoms, halogen, NO₂, CH₃O, CH₃, CH₂O, CH₃CH₂CH₂O.

In preferred compounds according to the invention, R represents astraight or branched chain alkyl group having 1 to 4 carbon atoms whichmay be substituted with one or more groups R₁, selected from Cl, NO₂,CH₃O. In other preferred embodiments, R is a phenyl or benzyl grouphaving one or two substituents R₂, selected from a straight or branchedchain alkyl group having 1 to 4 carbon atoms, Cl, NO₂, CH₃O. Suitablecompounds of the invention described in Table 1 (infra).

In the course of synthesis of the 9-substituted-1,5-dichloroanthracenes,it was found that the molecule reacted to the acylating agents in anunusual manner. Introduction of the 9-acyloxy functionality onto theanthracene nucleus (compounds 3a—w) was achieved by reaction of theappropriate acyl chlorides with 1,5-dichloroanthrone under weakly basicconditions, e.g. pyridine, where ester formation takes place at the C-9oxygen via the enol tautomer (FIG. 2).

For the pharmaceutical compositions according to the invention, salts of9-substituted-1,5-dichloroanthracene compounds are in particular saltswith the pharmaceutically acceptable base. Excipients such as magnesiumstearate, corn starch, starch, lactose, sodium hydroxymethylcellulose,ethanol, glycerol etc. may be added in the preparation of pharmaceuticalcompositions containing 1,5-dichloro-9-acyloxyanthracene derivatives ofthe present invention. The pharmaceutical compositions of the inventionmay be in an injectable form or formulated into tablet, pill or othersolid preparation forms. The pH value for injectable forms may beadjusted with phosphate buffer. Generally, dosage used for injectableforms is 25-100 mg. For solid preparations, an effective dosage is 3-500mg, administered 2 to 3 times a day.

Clinical Indications Subject to Treatment

The following conditions are selected for description herein as beingrepresentative of inflammatory, allergic, antioxidant, or neoplasticconditions that are suitable for treatment according to the practice ofthe invention. Each of these conditions involves intimationhyperproliferation and/or generation of free radicals and active oxygenspecies.

Neoplastic Conditions

The therapeutic compositions of the invention may be used in thetreatment of a wide variety of cancers such as carcinomas, sarcomas,melanomas and lymphomas, which may affect a wide variety of organs,including, for example, the lungs, mammary tissue, prostate gland, smallor large intestine, liver, heart, skin, pancreas and brain. Thetherapeutic compositions may be administered by injection(intravenously, intralesionally, peritoneally, subcutaneously), or bytopical application and the like as would be suggested according to theroutine practice of the art.

Psoriasis and Contact Dermatitis

Psoriasis is a widespread, chronic, inflammatory and scaling skindisease. Contact dermatitis, in contrast, is a short term allergiccondition characterized by scaling skin. Both psoriasis and contactdermatitis are characterized by increased epidermal cell proliferationat the affected site or sites, i.e. lesions. Muller, K., et al., J. Med.Chem., 39, 3132-3138 (1996).

Arthritic Disease

Rheumatoid arthritis is a chronic inflammatory disease, primarily of thejoints, that may result in permanent loss of joint function.Irreversible loss of joint function is attributed to severe degradationof collagen, bone, ligament and tendon. Associated chronic intimationresults, in part, from immune response at the affected joint, althoughthe exact nature of the triggering antigens is unknown. The immuneresponse may be autoimmune in origin. Mullins, D. E. and Rohrlich, S.T., Biochemica et Biophysica Acta, 695, 177-214 (1983). The etiology hasbeen described is in detail. (pp. 192-193.) Briefly, there is aprogressive loss of cartilage (a connective tissue) caused by invadingcells. Both collagen and proteoglycan components of the cartilage aredegraded by enzymes released at the affected site.

Therapeutic Compositions and Administration Thereof

The amount of 9-substituted-1,5-dichloroanthracene (or salt thereof)administered for the prevention or inhibition of an inflammatory orallergic condition, for antiproliferative or antineoplastic effect, canbe determined readily for any particular patient according to recognizedprocedures. Additional information useful in the selection oftherapeutic compositions is provided as follows. For use in thetreatment of inflammatory or degenerative conditions, as those term arerecognized in the art, the therapeutic compositions may be administered,for example, by injection at the affected site, by aerosol inhalation(as in the case of emphysema or pneumonia), or by topical application ortransdermal absorption as would also be suggested according to theroutine practice of the art.

As described above, the 9-substituted-1,5-dichloroanthracene (or saltthereof) may be incorporated into a pharmaceutically acceptable carrieror carriers for application (directly or indirectly) to the affectedarea. The nature of the carrier may vary widely and will depend on theintended location of application and other factors well known in theart. Such carriers of anthralin or anthracenone compounds are well knownin the art. See, for example, Kammerau, B. et al., J. InvestigativeDermatology, 64, 145-149 (1975).

Preparation of the Compounds of the Invention

FIG. 2 is an outline of a synthesis of the9-substituted-1,5-dichloroanthracene compounds (Formula III) accordingto the invention. As shown in FIG. 2, reduction of1,5-dichloroanthraquinone (1) with SnCl₂ in boiling HCl and acetic acidproceeds with concomitant ether cleavage and leads to the corresponding1,5-dichloro-9(10H)-anthracenone (II). In the course of synthesis of the9-substituted-1,5-dichloroanthracene, it was found that the moleculereacted to the acylating agents in an unusual manner. Introduction ofthe 9-acyloxy functionality onto the anthracene nucleus (compounds 3a-w)was achieved by reaction of the appropriate acyl chlorides with1,5-dichloro-9(10H)-anthrone under weakly basic conditions (pyridine),resulting in ester formation at the C-9 position via the enol tautomer(FIG. 2). When the anthrone was allowed to react with acyl chlorides inCH₂Cl₂ in the presence of a catalytic amount of pyridine, the reactiontime is reduced compared to the noncatalyzed reaction. Specific methodsfor the preparation of several compounds according to the presentinvention are described below in Example 1. The structure of each of thesynthesized compounds is confirmed by ¹H-NMR spectrometry, massspectrometry and elemental analysis as shown in Example 2. Proceduresadapted from the descriptions and the following non-limiting exampleswill allow one skilled in the art to prepared similar compounds of theinvention.

EXAMPLES

The following non-limiting examples are representative of the practiceof the invention.

Example 1 Methods of Synthesis

The novel 9-substituted-1,5-dichloroanthracene compounds described inTable 1 were produced as follows.

1,5-dichloroanthraquinone (1) was reduced with SnCl₂ in boiling HCl andacetic acid with ether cleavage to give the corresponding 1,5dichloro-9(10H)-anthracenone (II). To a solution of1,5-dichloro-9(10H)anthracenone (1 mmol) and 0. 1 mL of pyridine in dryCH₂Cl₂ (20 mL) was added dropwise a solution of an appropriate acylchloride (3 mmol) in dry CH₂Cl₂ (10 mL) under N₂. The reaction mixturewas stirred at room temperature or refluxed for several hours. Thesolvent was removed and the residue purified by recrystallization andchromatography. This procedure was used to synthesize each of thecompounds in Table 1.

Example 2 Structural Confirmation

All temperatures are reported in degrees centigrade. Melting points weredetermined with a Büchi 530 melting point apparatus and are uncorrected.Chromatography refers to column chromatography using silica gel (E.Merck, 70-230 mesh). ¹H-NMR spectra were recorded with a VarianGEMR-H-300 (300 MHz); δ values are in ppm relative to atetramethylsilane internal standard. Fourier-transform IR spectra (KBr)were recorded on a Perkin-Elmer 983G spectrometer. Mass spectra (EI, 70eV, unless otherwise stated) were obtained on a Finnigan MAT TSQ-46 andFinnigan MAT TSQ-700. UV spectra were recorded on a Shimadzu UV-160.

(1) 1,5-Dichloro-9-acetyloxy-anthracene (3a)

The compound was synthesized as in Example 1 and analyzed by ¹H-NMR (500MHz CDCl₃), δ (ppm): 8.79 (H, s, H-10), 8.01 (H, d, J=8.4 Hz, H-2), 7.90(H, d, J=8.8,H6), 7.62-7.58 (2H, m, H-4,8), 7.43-7.34 (2H, m, H-3,7),2.60 (3H, s, COCH₃); ¹³C-NMR: (75 MHz, CDCl₃), δ (ppm): 170.58, 142.00,134.51, 132.31, 130.54, 129.87, 129.61, 128.37, 126.97, 126.93, 126.80,125.97, 123.81, 121.79, 121.67, 22. 1; MS m/z 304 (7), 262 (100); Anal.(Cl₁₆H₁₀O₂Cl₂); C, H.

(2) 1,5-Dichloro-9-benzoyloxy-anthracene (3L)

The compound was synthesized as in Example 1 and analyzed by ¹H-NMR:(500 MHz, CDCl₃), δ (ppm): 8.82 (H, s, H-10), 8.40 (2H, d, J=8.1 Hz,H-2′,6′), 8.01 (2H, d, J=8.4 Hz, H-2), 7.91 (H, d, J=8.8 Hz, H-6), 7.71(H, t, J 7.5 Hz, H-4′), 7.61-7.58 (2H, m, H-4,8), 7.56-7.52 (2H, d,J=7.2 Hz, H-3′,5′), 7.37-7.33 (2H, m, H-3,7); ¹³C-NMR: (75 MHz, CDCl₃),δ (ppm): 166.62, 142.41, 134.49, 132.64, 131.28, 130.43, 130.11, 129.98,129.53, 129.40, 128.65, 127.24, 126.98, 126.00, 125.84, 122.45, 121.81;MS m/z 367 (10), 262 (7), 246 (4), 227 (5), 105 (100); Anal.(C₂₁H₁₂O₂Cl₂); C, H.

(3) 1,5-Dichloro-9-(m-toluyloxy)-anthracene (3n)

The compound was synthesized as in Example 1 and analyzed by ¹H-NMR:(500 MHz, CDCl₃), δ (ppm): 8.74 (H, s, H-10), 8.15 (H, d, J=7.4 Hz,H-2′,6′), 7.93 (H, d, J=8.8,H-2), 7.85 (H, dd, J=8.8, 0.9 Hz, H-6),7.53-7.48 (2H, m, H-4,8), 7.46-7.39 (2H, m, H-4′,5′), 7.29-7.25 (2H, m,H-3,7), 2.42 (3H, S, COCH₃); ¹³C-NMR: (75 MHz, CDCl₃), δ (ppm): 166.41,142.98, 139.28, 135.31, 134.55, 132.58, 131.83, 130.40, 129.94, 129.90,129.52, 129.31, 128.72, 128.55, 127.19, 126.94, 126.00, 123.79,122.38,121.86,21.97; MS m/z 381 (13), 119 (100); Anal. (C₂₂H₁₄O₂Cl₂); C,H.

(4) 1,5-Dichloro-9-(p-toluoxy)-anthracene (3o)

The compound was synthesized as in Example I and analyzed by ¹H-NMR:(500 MHz, CDCl₃), δ (ppm): 8.81 (H, s, H-10), 8.28 (2H, d, J=8.1 Hz,H-2′,6′), 8.01 (H, d, J=8.4 Hz, H-4), 7.91 (H, d, J=8.8,H-5′), 7.36-7.32(2H, m, H-3,7), 2.58 (3H, s, CH₃); ¹³C-NMR: (75 MHz, CDCl₃), δ (ppm):166.28, 145.43, 143.43, 134.56, 132.56, 131.43, 130.38, 130.13, 129.91,129.51, 128.76, 127.28, 127.24, 126.97, 126.91, 125.99, 123.74, 122.49,121.89, 22.44; MS m/z 380 (4), 119 (100); Anal. (C₂₂H₁₄O₂Cl₂); C, H.

The perspective view of the molecular structure of compound (3o) isshown in FIG. 3.

Example 3 Growth Inhibition Assay

Growth inhibition was measured in three human carcinoma cell lines (GBKKB and CHO) using a previously described in vivo assay. Hwang, J.-M. etal., Chin. Med. J (Taipei), 51, 166-175 (1993). Human oral epidermoidcarcinoma cells (KB cell line), human cervical carcinoma cells of ME 180(GBM8401) and Chinese hamster ovary (CHO) cells grown in plateau phasewere used in all experiments. Each cell line was further divided intocontrol and experimental groups, respectively.

Stock solutions of the test compounds were prepared in DMSO and dilutedwith DMEM to give a final concentration of DMSO of 0.2%. Controls wereperformed with DMSO or with medium alone. The medium was removed andeach well was rinsed with 100 μL PBS 48 hours after addition of the testcompound to the culture. The cells were then incubated with sterile 0.5%trypsin, 0.2% EDTA in PBS for 20 minutes at 37° C. The detached cellsfrom each well were suspended in DMEM and dispersed into single cells bygentle pipeting through an Eppendorf pipette and cell growth wasdetermined directly by counting the cells in a Neubauer counting chamberusing phase contrast microscopy. Inhibition was calculated by comparisonof the mean values of the test compound (N=3) with the control (N=6−8)activity: (1-test compound/control) ×100. Inhibition was statisticallysignificant compared to that of control (Student's t Test; P=0.05). IC₅₀values (concentration required to inhibit cell growth by 50%) weredetermined for each agent which was derived by interpolation of a loginhibitor concentration versus response plot using four or moredifferent concentrations of the compound spanning the 50% inhibitionpoint.

Several compounds of the invention had an antiproliferative IC₅₀ valueof less than 1.1 μM for GBM cell line. In particular, compounds 3g, 3jand A had IC₅₀ values of 1.4, 1.1 and 1.2 μM respectively. In addition,each of compounds 3j and 3v showed an IC₅₀ value of 11.0 μM and 12.6 μMin the KB assay. The results of this assay are provided in Table 1.

Example 4 Taq Polymerase Assay

Prior to the evaluation of compounds in the PCR-based telomerase assay,the agents were tested for their ability to inhibit Taq polymerase inorder to address the selectivity of polymerase/telomerase inhibition.Compounds were included at both 10 and 50 μM final concentrations in aPCR 50 μL master mix comprising 10 ng of pCI-neo mammalian expressionvector (Promega, Southampton, U.K.), forward (CGAGTTCCGCGT-TACATAAC) andreverse (GTCTGCTCGAAGCATTAACC) primers (200 nmol), reaction buffer (75mM Tris-HCl, pH 8.81, 20 mM (NH₄)₂SO₄, 0.01% v/v Tween 20), 2.5 mMMgCl₂, 200 μM of each deoxynucleotide triphosphate, and thermostable DNApolymerase (“red hot”, Advanced Biotechnologies, 1.25 units). A reactionmix containing water and no drug was used as a positive control,producing a product of approximately 1 kb. Amplification (30 cycles of94° C. for 1 min, 55° C. for 1 min, and 72° C. for 2.5 min) wereperformed using a thermal cycler (Hybaid, U.K.). PCR products were thenseparated by electrophoresis on a 2% w/w agarose gel and visualizedusing ethidium bromide. The results of this assay are provided in Table2.

Example 5 Lipid Peroxidation Assay

Rat brain homogenate was prepared from the brains of freshly killedWistar rats and its peroxidation. In the presence of iron ions wasmeasured by the thiobarbituric acid (TBA). Teng, C. M. et al., Eur. J.Pharmacol., 303, 129-139 (1996). Tetramethoxypropane was used as astandard, and the results were expressed as nanomoles of malondialdehydeequivalents per milligram of protein of rat brain homogenates.

In brief, whole brain tissue, excluding the cerebellum, was washed andhomogenized in 10 volumes of ice-cold Krebs buffer (10 mM N-2hydroxyethyl-piperazine-N′-2-ethanesulfonic acid (Hepes), 10 mM glucose,140 mM NaCl, 3.6 mM KCl, 1.5 mM CaCl₂, 1.4 mM KH₂PO₄, 0.7 mM MgSO₄, pH7.4) using a glass Dounce homogenizer. The homogenate was centrifuged atlow speed (1000×g) for 10 min, and the resulting supernatant (adjustedto 2 mg/mL) was used immediately in lipid. peroxidation assays.

The reaction mixture with test compounds or vehicle was incubated for 10min, then stimulated by addition of ferrous ion (200 μM freshlyprepared), and maintained at 37° C. for 30 min. The reactions wereterminated by adding 10 μM of ice-cold trichloroacetic acid solution (4%(w/v) in 0.3 N HCl) and 200 μM, of thiobarbituric acid-reactivesubstance reagent (0.5% (w/v) thiobarbituric acid in 50% (v/v) aceticacid). After boiling for 15 min, the samples were cooled and extractedwith n-butanol. The extent of lipid peroxidation was estimated asthiobarbituric acid-reactive substances and was read at 532 nm in aspectrophotometer (Shimadzu UV-160). The results of this assay areprovided in Table 3.

The contents of all patents, patent applications, published articles,books, reference manuals and abstracts cited herein are herebyincorporated by reference in their entirety to more fully describe thestate of the art to which the invention pertains.

As various changes can be made in the above-described subject matterwithout departing from the scope of the invention, it is intended thatall subject matter contained in the above description, shown in theaccompanying drawing, or defined in the appended claims, be interpretedas descriptive, illustrative, and non-limiting. Modifications andvariations of the present invention are possible in light of the aboveteachings. It is therefore to be understood that within the scope of theappended claims, the invention may be practiced otherwise than asspecifically described.

TABLE 1 In vitro cytotoxicity data for novel 1,5-dichloroanthracenecompounds of the invention Comp'd mp IC₅₀(μM)^(a) No. R group Formula MW(° C.) GBM KB CHO 3a CH₃ C₁₆H₁₀O₂Cl₂ 305.16 164-166 48.1 472.8 114.5 3bCH₂Br C₁₆H₉O₂Cl₂Br 384.06 180-181 19.2 136.0 1012.8 3c CH₂Cl C₁₆H₉O₂Cl₃339.60 181-182 105.6 527.5 1.2 3d CH₂CH₃ C₁₇H₁₂O₂Cl₂ 319.18 134-135 17.2470.8 1157.6 3e CH(CH₃)₂ C₁₈H₁₄O₂Cl₂ 332.17 116-118 195.5 430.8 1314.23f CH(CH₃)Cl C₁₇H₁₁O₂Cl₃ 353.63 120-122 125.8 374.1 954.9 3g CHCl₂C₁₆H₈O₂Cl₄ 374.05 138-140 1.4 527.8 1277.9 3h (CH₂)₂CH₃ C₁₈H₁₄O₂Cl₂333.21 132-134 572.2 544.3 0.1 3i (CH₂)₃Br C₁₈H₁₃O₂BrCl₂ 412.11 118-120205.2 457.3 109.9 3j (CH₂)₃Cl C₁₈H₁₃O₂Cl₃ 367.65 130-132 1.1 11.0 1171.33k (CH₂)₄CH₃ C₂₀H₁₈O₂Cl₂ 361.26 120-121 1.2 316.8 55.1 3L C₆H₅C₂₁H₁₂O₂Cl₂ 367.23 166-168 226.3 813.2 1437.2 3m 2-CH₃C₆H₄ C₂₂H₁₄O₂Cl₂381.26 162-164 107.9 1136.4 1513.3 3n 3-CH₃C₆H₄ C₂₂H₁₄O₂Cl₂ 381.26172-173 397.9 110.9 1199.2 3o 4-CH₃C₆H₄ C₂₂H₁₄O₂Cl₂ 381.26 204-206 11.2865.2 11639 3p 3-ClC₆H₄ C₂₁H₁₁O₂Cl₃ 401.67 172-174 11.7 1050.6 19840 3q4-ClC₆H₄ C₂₁H₁₁O₂Cl₃ 401.67 169-171 —^(b) —^(b) —^(b) 3r 4-NO₂C₆H₄C₂₁H₁₁NO₄Cl₂ 412.22 198-200 —^(b) —^(b) —^(b) 3s 3-NO₂C₆H₄ C₂₁H₁₁NO₄Cl₂412.22 216-218 11.1 836.6 1481.7 3t 4-Cl C₂₂H₁₃O₃Cl₃ 431.70 195-196 10.8818.1 114.5 2-CH₃O—C₆H₃ 3u 2,4-Cl₂C₆H₃ C₂₂H₁₀O₂Cl₄ 436.12 190-192 87.7107.5 1182.7 3v CH₂C₆H₅ C₂₂H₁₄O₂Cl₂ 381.25 152-154 109.8 12.6 1186.7 3wCH₂CH₂C₆H₅ C₂₃H₁₆O₂Cl₂ 395.28 126-128 1734.8 936.3 1164.7 Doxorubicin598.9 420.5 498.8 Mitomycin-C 1896.3 11720 2122.5 Methotrexate 9286.247180 9141.5 ^(a)Concentration required to inhibit cell growth by 50%relative to controls. ^(b)Not dissolved.

TABLE 2 Taq inhibition data for novel 1,5-dichloro-anthracenes Comp'dTaq Inhibition No. R group 1 mM 0.1 mM 0.01 mM 3b CH₂Br + + + 3c CH₂Cl −− − 3d CH₂CH₃ + + + 3g CHCl₂ + + + 3h (CH₂)₂CH₃ + + + 3i (CH₂)₃Br − − −3j (CH₂)₃Cl + + − 3k (CH₂)₄CH₃ + + + 3m 2-CH₃C₆H₄ + − − 3n 3-CH₃C₆H₄ + +− 3p 3-ClC₆H₄ + − − 3q 4-ClC₆H₄ + − − 3r 3-NO₂C₆H₄ − − − 3s 4-NO₂C₆H₄ −− − 3u 2,4-Cl₂C₆H₃ + + − 3v CH₂C₆H₅ + + − 3w CH₂CH₂C₆H₅ + + +

TABLE 3 Inhibitory effects of novel 1,5-dichloro-anthracene compounds ofthe invention on iron-induced lipid peroxidation in rat brainhomogenates % Inhibition^(a) % Inhibition^(a) Comp'd No. R group (10 μM)(1 μM) 3a CH₃ 34.4 25.5 3b CH₂Br 100 100 3c CH₂Cl 100 100 3d CH₂CH₃ 100100 3e CH(CH₃)₂ 28.6 1.5 3f CH(CH₃)Cl 60.6 9.8 3g CHCl₂ 100 61.7 3h(CH₂)₂CH₃ 17.7 11.8 3i (CH₂)₃Br 100 38.1 3j (CH₂)₃Cl 29.0 10.0 3k(CH₂)₄CH₃ 17.2 12.2 3L C₆H₅ 14.0 4.6 3m 2-CH₃C₆H₄ 23.0 0 3n 3-CH₃C₆H₄22.4 10.9 3o 4-CH₃C₆H₄ 25.6 2.9 3p 3-ClC₆H₄ 30.6 8.6 3q 4-ClC₆H₄ —^(b)—^(b) 3r 4-NO₂C₆H₄ —^(b) —^(b) 3s 3-NO₂C₆H₄ 35.7 5.9 3t 4-Cl, 10.3 02-CH₃O—C₆H₃ 3u 2,4-Cl₂C₆H₃ 16.0 1.7 3v CH₂C₆H₅ 32.8 13.7 3w CH₂CH₂C₆H₅36.6 29.3 (+)-a-Tocopherol 100 61.6 ^(a)Relative percentage ofinhibition ^(b)Not dissolved.

What is claimed is:
 1. A pharmaceutical compound according to FormulaIII,

wherein R is selected from the group consisting of a straight orbranched chain alkyl group having 1 to 6 carbons substituted with one ormore R₁ groups, a benzyl group, a phenyl group which is substituted withone or two R₂ groups, and a benzyl group which is substituted with oneor two R₂ groups; wherein R₁ is selected from the group consisting ofhalogen, —NO₂, —OCH₃, OCH₂CH₃, and —OCH₂CH₂CH₃; and wherein R₂ isselected from the group consisting of a straight or branched chain alkylgroup having 1 to 4 carbons, halogen, —NO₂, —OCH₃, —OCH₂CH₃, and—OCH₂CH₂CH₃.
 2. The compound according to claim 1, wherein R representsa substituted phenyl group selected from the group consisting of2—CH₃C₆H₄ , 3—CH ₃C₆H_(4,) 4—CH ₃C₆H_(4,) 3—ClC ₆H_(4,) 4—ClC ₆H₄,3—NO₂C₆H₄, 4—NO₂C₆H₄, 4—Cl—2—CH₃OC₆H₃, and 2,4—Cl₂C₆H₃.
 3. The compoundaccording to claim 1, wherein R represents a substituted alkyl groupselected from the group consisting of CH₂Br, CH₂Cl, CH(CH₃)Cl, CHCl₂,(CH₂)₃Br, and (CH₂)₃Cl.
 4. An anti-inflammatory drug, comprising, as anactive ingredient, the pharmaceutical compound of claim
 1. 5. Anantioxidant, comprising, as an active ingredient, the pharmaceuticalcompound of claim
 1. 6. An anti-dermatitis cancer drug, comprising, asan active ingredient, the pharmaceutical compound of claim
 1. 7. Acompound having the chemical structure of Formula III,

wherein R represents a phenyl or benzyl group having one or twosubstituents which is selected from the group of methyl, NO₂, OCH₃ andCl.
 8. A compound having the chemical structure of Formula III,

wherein R is CH₂C₆H₅ or CH₂CH₂C₆H₅.
 9. A method for synthesis of9-substituted-1, 5-dichloroanthrecene compounds and salts thereof,comprising reacting 1, 5-dichloroanthrone with an acyl chloride underweakly basic conditions to give the 9-subsituted-1,5-dichloroanthrancene according to Formula III

wherein R is selected from the group consisting of a straight chainalkyl group having 1 to 6 carbons which is optionally substituted withone or more R₁groups, a branched chain alkyl group having 1 to 6 carbonswhich is optionally substituted with one or more R₁ groups, —CH₂CH₂C₆H₅,a phenyl which is substituted with one or more R₂ groups, and a benzylgroup which is optionally substituted with one or two R₂ groups; whereinR₁ is selected from the group consisting of halogen, —NO₂, —OCH₃,OCH₂CH₃, and —OCH₂CH₂CH₃; and wherein R₂ is selected from the groupconsisting of a straight or branched chain alkyl group having 1 to 4carbons, halogen, —NO₂, —OCH₃, —OCH₂CH₃, and —OCH₂CH₂CH₃.
 10. The methodof claim 9 wherein the weakly basic condition is accomplished by theaddition of pyridine.
 11. A pharmaceutical compound which is synthesizedby reacting 1,5-dichloroanthrone with an acyl chloride of the formRC(O)Cl under a weakly basic condition; wherein R is selected from thegroup consisting of a straight chain alkyl group having 1 to 6 carbonswhich is substituted with one or more R₁ groups, a branched chain alkylgroup having 1 to 6 carbons which is optionally substituted with one ormore R₁ groups, —CH₂CH₂C₆H₅, a benzyl group, a phenyl group which issubstituted with one or two groups R₂, and a benzyl group which issubstituted with one or two groups R₂; wherein R₁ is a group selectedfrom halogen, —NO₂, —OCH₃, —OCH₂CH₃, and —OCH₂CH₂CH₃; wherein R₂ is agroup selected from a straight or branched chain alkyl group having 1 to4 carbons, halogen, —NO₂, —OCH₃—OCH₂CH₃, and —OCH₂CH₂CH₃; and whereinsaid weakly basic condition is accomplished by the addition of pyridine.12. The pharmaceutical compound according to claim 11, wherein the acylchloride is benzoyl chloride or a substituted benzoyl chloride which isselected from the group consisting of 2-methylbenzoyl chloride,3-methylbenzoyl chloride, 4-methylbenzoyl chloride, 3-chlorobenzoylchloride, 4-chlorobenzoyl chloride, 3-nitrobenzoyl chloride,4-nitrobenzoyl chloride, 4-chloro-2-methoxybenzoyl chloride and2,4-dichlorobenzoyl chloride.
 13. The pharmaceutical compound accordingto claim 11, wherein the acyl chloride is phenylacetyl chloride or asubstituted phenylacetyl chloride having a substituent selected from thegroup consisting of methyl, nitro, methoxy and chloro.
 14. Thepharmaceutical compound according to claim 11, wherein the acyl chlorideis bromoacetyl chloride, chloroacetyl chloride, propanoyl chloride,isobutyryl chloride, 2-chloropropanoyl chloride, dichloroacetylchloride, butyryl chloride, 4-bromobutyrlyl chloride, 4-chlorobutyrlylchloride, 3-phenylpropanoyl chloride or hexanoyl chloride.
 15. Thepharmaceutical compound according to claim 11, wherein the acyl chlorideis benzoyl chloride and having a ¹H-NMR characterized by signals at δ(ppm relative to tetramethyl silane) of approximately 8.82 (s), 8.40(d), 8.01 (d), 7.91 (d), 7.71 (t), 7.61-7.58 (m), 7.56-7.52 (d),7.37-7.33 (m), wherein s, d, t and m designate signals comprising asinglet, a doublet, a triplet, and a multiplet, respectively.
 16. Thepharmaceutical compound according to claim 11, wherein the acyl chlorideis 3-methylbenzoyl chloride and having a ¹H-NMR characterized by signalsat δ (ppm relative to tetramethyl silane) of approximately 8.74 (s),8.15 (d), 7.93 (d), 7.85 (dd), 7.53-7.48 (m), 7.46-7.39 (m), 7.29-7.25(m), 2.42 (s) wherein s, d, dd and m designate signals comprising asinglet, a doublet, a doublet of doublets, and a multiplet,respectively.
 17. A method for anti-cancer treatment, comprisingadministering a therapeutically effective amount of a pharmaceuticalcompound according to claim 11 or a pharmaceutically acceptable salt ofsaid compound and optionally a pharmaceutical carrier to a patient inneed of such treatment.
 18. A method for treating abnormalproliferation, comprising administering a therapeutically effectiveamount of a pharmaceutical compound according to claim 11 or apharmaceutically acceptable salt of said compound and optionally apharmaceutical carrier to a patient in need of such treatment.
 19. Amethod for enhancing an anti-oxidation affect, comprising administeringa therapeutically effective amount of a pharmaceutical compoundaccording to claim 11 or a pharmaceutically acceptable salt of saidcompound and optionally a pharmaceutical carrier to a patient in need ofsuch treatment.
 20. An anti-cancer drug, comprising, as an activeingredient, the pharmaceutical compound of claim
 11. 21. Ananti-inflammatory drug, comprising, as an active ingredient, thepharmaceutical compound of claim
 11. 22. An antioxidant, comprising, asan active ingredient, the pharmaceutical compound of claim
 11. 23. Ananti-dermatitis cancer drug, comprising, as an active ingredient, thepharmaceutical compound of claim
 11. 24. A method for inhibiting ortreating an allergic or inflammatory condition, comprising administeringa therapeutically effective amount of a pharmaceutical compoundaccording to claim 11 or a pharmaceutically acceptable salt of saidcompound and optionally a pharmaceutical carrier to a patient in need ofsuch treatment.
 25. A method for inhibiting or treating an allergic orinflammatory condition, comprising administering to a patient atherapeutically effective amount of a pharmaceutical compound having thechemical structure of Formula III,

wherein R represents a straight or branched chain alkyl group having 1to 6 carbons which may be substituted with one or more grous R₁, or Rrepresents a a benzyl group, a phenyl group which may be substitutedwith one or two R₂ groups, and a benzyl group which is substituted withone or two R₂ groups; wherein R₁ is selected from the group consistingof halogen, —NO₂, —OCH₃, OCH₂CH₃, and —OCH₂CH₂CH₃; and wherein R₂ isselected from the group consisting of a straight or branched chain alkylgroup having 1 to 4 carbons, halogen, —NO₂, —OCH₃, —OCH₂CH₃, and—OCH₂CH₂CH₃.
 26. A method for anti-cancer treatment, comprisingadministering a therapeutically effective amount of a pharmaceuticalcompound or a pharmaceutically acceptable salt of said compound andoptionally a pharmaceutical carrier to a patient in need of suchtreatment, wherein said pharmaceutical compound has the chemicalstructure of Formula III according to claim
 25. 27. A method fortreating abnormal proliferation, comprising adminstering atherapeutically effective amount of a pharmaceutical compound or apharmaceutically acceptable salt of said compound and optionally apharmaceutical carrier to a patient in need of such treatment, whereinsaid pharmaceutical compound has the chemical structure of Formula IIIaccording to claim
 25. 28. A method for enchancing an anti-oxidanteffect, comprising adminstering a therapeutically effective amount of apharmaceutical compound or a pharmaceutically acceptable salt of saidcompound and optionally a pharmaceutical carrier to a patient in need ofsuch treatment, wherein said pharmaceutical compound has the chemicalstructure of Formula III according to claim 25.